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Sorafenib hemi-p-tosylate monohydrate crystal and preparation process thereof

Inactive Publication Date: 2018-12-27
CHIA TAI TIANQING PHARMA GRP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is a new type of sorafenib hemi-p-tosylate monohydrate crystal that has high stability, low hygroscopicity, high purity, and high degree of crystallinity. The process for preparing this crystal is simple and easy, uses a cheap and available solvent, and has mild crystallization conditions, making it suitable for industrial production.

Problems solved by technology

Therefore, such processes cannot meet the requirement for a large-scale industrial production.

Method used

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  • Sorafenib hemi-p-tosylate monohydrate crystal and preparation process thereof
  • Sorafenib hemi-p-tosylate monohydrate crystal and preparation process thereof
  • Sorafenib hemi-p-tosylate monohydrate crystal and preparation process thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

on of Sorafenib Hemi-p-Tosylate Monohydrate

[0041]At a room temperature, to a reaction tank were added anhydrous ethanol (85.6 kg) and purified water (11.9 kg), and then sorafenib (10.84 kg, 23.32 mol) were added under stirring. After stirring for 10 min, p-toluenesulfonic acid monohydrate (2.38 kg, 12.51 mol) was added at one time. The resulting mixture was crystallized for 8 hours under stirring, and then filtrated under centrifugation. The resulting solid was dried for 10 hours at a temperature of 6035° C. under vacuum to obtain sorafenib hemi-p-tosylate monohydrate (11.48 kg, yield: 89.5% and purity: 99.96%).

[0042]Its X-ray powder diffraction pattern using Cu Kα irradiation was shown in FIG. 1, differential scanning calorimetry (DSC) pattern was shown in FIG. 2, and thermogravimetric analysis (TGA) pattern was shown in FIG. 3.

[0043]Element analysis: C: 51.64% (theoretical value: 51.72%), H: 3.98% (theoretical value: 3.90%), N: 9.83% (theoretical value: 9.85%), S: 2.85% (theoretic...

example 2

ase Condition for HPLC Analysis of Sorafenib Hemi-p-Tosylate Monohydrate

[0044]Chromatographic column: Agilent peptide map chromatographic column (3.0×150 mm, 2.7 μm)

[0045]Mobile phase A: phosphate buffer solution (monopotassium phosphate (0.79 g) was weighted and dissolved in water, then diluted to 1000 ml, and further adjusted to pH=2.4 with phosphoric acid)

[0046]Mobile phase B: ethanol-acetonitrile (40:60)

[0047]Detection wavelength: 235 nm for detection

[0048]Flow rate: 0.6 ml / min

[0049]Column temperature: 55° C.

[0050]Injection volume: 10 μl

[0051]Solvent: mobile phase A-mobile phase B (1:3)

[0052]Preparation of a solution of a test sample: an appropriate amount of the test sample was weighted and dissolved in the solvent [mobile phase A-mobile phase B (1:3)], then diluted to a solution which comprises about 0.16 mg of sorafenib per 1 ml as the solution of the test sample.

[0053]A linear gradient elution was performed according to the program as shown in Table 3:

TABLE 3Test condition f...

example 3

Test

[0054]The stability test for the sorafenib hemi-p-tosylate monohydrate crystal of the present invention was conducted according to the Chinese Pharmacopoeia (2010), Part 11, Appendix XIX C: Guideline for Stability Test of Bulk Drug and Pharmaceutical Preparation. The results were shown in Table 4.

TABLE 4Results of stability testExposure testto lightShading testStanding for 6StandingStandingStanding for 10(luminance:(luminance:months at 25° C. ±for 10for 10days at 25° C.6000 Lux),6000 Lux),2° C. anddays atdays atand humidity ofstanding forstanding forhumidity ofDay 040° C.60° C.92.5% ± 5%10 days10 days60% ± 5%Purity99.96%99.96%99.95%99.96%99.97%99.96%99.96%

[0055]The results in the above table showed that the sorafenib hemi-p-tosylate monohydrate of the present invention is highly stable, and therefore particularly suitable for a pharmaceutical preparation.

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Abstract

The present invention relates to the field of medicinal technology, and in particular, to sorafenib hemi-p-tosylate monohydrate crystal and preparation process thereof. The crystal has diffraction peaks occurring at 2θ angle of about 5.62, 6.67, 8.05, 9.06, 9.63, 9.91, 10.95, 11.25, 13.48, 14.00, 14.60, 15.08, 15.75, 16.20, 16.62, 16.80, 17.23, 18.40, 18.97, 19.32, 19.82, 20.49, 20.74, 21.51, 22.56, 22.86, 23.37, 23.71, 24.20, 24.71, 24.97, 25.54, 25.80, 26.18, 27.14, 27.48, and 28.29 degree in a X-ray powder diffraction pattern, and some advantages, such as a high stability, a low hygroscopicity and the like.

Description

TECHNICAL FIELD[0001]The present invention relates to the field of medicinal technology, and in particular, to sorafenib hemi-p-tosylate monohydrate crystal and preparation process thereof.BACKGROUND TECHNOLOGY[0002]Sorafenib tosylate has the structure represented by formula (1), and its chemical name is 4-{4-[3-(4-chloro-3-(trifluoromethyl)-phenyl)-ureido]-phenoxy}-N-methyl pyridine-2-carboxamide 4-methylbenzenesulfonate. Sorafenib is developed and marketed by Bayer and Onyx. Sorafenib is an oral small-molecule kinase inhibitor for inhibiting a cell growth, is used for treating renal cell carcinoma (RCC) and unresectable hepatocellular carcinoma (HCC).[0003]CN101052619, WO2009034308 and US20130005980 disclose a process for preparing sorafenib tosylate. CN101065360 discloses three crystals of sorafenib tosylate (I, II, and III), and their corresponding preparation processes. In order to obtain a stable crystal, a crystal transformation with stirring at a high temperature or for a lo...

Claims

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Application Information

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IPC IPC(8): C07D213/81A61P35/00
CPCC07D213/81A61P35/00
Inventor WU, SHUFENGZHANG, AIMINGZHANG, XIQUANZHU, XUEYAN
Owner CHIA TAI TIANQING PHARMA GRP
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